Novel one-two punch treatment strategy shows promise in preclinical models of advanced prostate cancer

 

• Results of a study led by VHIO’s Prostate Cancer Group suggest that treatment with CDK4/6 inhibitors followed by senloytic therapies and PARP inhibitors could improve outcomes and combat cancer drug resistance in advanced prostate cancer.

 

• Published in Molecular Cancer Therapeutics, this work was funded by the Scientific Foundation of the Spanish Association Against Cancer (AECC).

 

With an estimated 1.5 million new cases and 397,000 deaths worldwide, prostate cancer is the world’s second most frequent cancer and the fifth leading cause of cancer death among men in 2022¹. Hormone therapy based on the inhibition of androgen receptor signalling (ARPi) is the mainstay of treatment for metastatic prostate cancer (mPC). However, cancer drug resistance ultimately arises, highlighting the need for more effective therapeutic strategies.

Aimed at overcoming drug resistance in prostate cancer treatment, one of VHIO’s Prostate Cancer Group key objectives is to advance insights into the genomic landscape and biology underpinning prostate cancer to expose novel vulnerabilities in tumor cells, develop new therapies, and optimize existing ones.  

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors constitute a promising therapeutic avenue for different tumor types, some of which have already been approved for the treatment of advanced estrogen receptor (ER)-positive breast cancer.  Despite promising results in preclinical models of mPC, particularly in studies combining them with other therapies, several clinical trials of CDK4/6i, as monotherapy or in combination, have generated negative results.

Funded by the Scientific Foundation of the Spanish Association Against Cancer (AECC), an innovative preclinical study led by Joaquin Mateo was designed to address the challenge of drug resistance associated with CDK4/6i in mPC from a new perspective. Instead of focusing solely on the direct effects of these drugs, they delved deeper into the changes in tumor cells induced by CDK4/6 inhibitors and thus sought to identify new therapeutic vulnerabilities.

An innovative sequential approach

Published in Molecular Cancer Therapeutics², results of this study show that following treatment with CDK4/6 inhibitors, a small subset of persistent tumor cells enter a hibernation-like state, called ‘dormancy’, to evade therapy. These dormant cancer cells can unfortunately ‘wake up’ years later, causing tumor relapse. The investigators showed that the combination of these inhibitors with senolytic therapies could prevent disease recurrence.

“In a range of in vitro and in vivo prostate cancer models, including patient-derived xenografts, our preclinical investigations show that CDK4/6 inhibitors halt the growth of prostate cancer cells and induce a senescent state, that can be targeted using senolytic therapies,” said Joaquin Mateo, a Medical Oncologist at the Vall d’Hebron University Hospital, co-leader of VHIO’s Prostate Cancer Group, and corresponding author of this study.

The researchers also reported that residual tumor cells show increased sensitivity to PARPi, a type of targeted cancer drug already approved for the treatment of prostate cancer. This observation opens the door to designing new sequential treatment strategies that combine both therapies to improve clinical outcomes.

Notably, in a second phase of their preclinical investigations, this sequential strategy also capitalizes on a second biological effect of CDK4/6 inhibitors on tumor cells, observing that when exposure to these drugs stop abruptly, tumor cells rapidly accumulate DNA damage.

“This effect opens a window of opportunity for treatment with PARP inhibitors. Upfront combined inhibition with CDK4/6 and PARP1 has no antitumor effect. However, their sequential use adding PARPi upon CDK4/6i withdrawal results in striking antitumor activity,” observed Julian Brandariz, a PhD Student of VHIO’s Prostate Cancer Group and first author of this work. 

“Our results demonstrate the potential of CDK4/6i in prostate cancer therapy, particularly when followed by sequential treatment with senolytic therapy or PARPi. This new one-two punch strategy holds promise in overcoming cancer drug resistance, improving treatment outcomes for metastatic prostate cancer, and open avenues for repurposing CDK4/6i therapy in metastatic prostate cancer,”  concluded Mateo.

These findings represent a step foward in personalizing and optimizing therapy for advanced prostate cancer and could provide new scientific rationale for the design of future clinical trials.

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References

1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263. 

 

2. Brandariz J, de Llobet LI, Esquefa V, Aguilar D, Salca A, Arce-Gallego S, Cresta Morgado P, Sole Casaramona A, Agundez Muriel L, Mir Arnau G, Castro N, Casals Galobart T, Oliveira Tercero A, Casanova-Salas I, Malumbres M, Carles J, Morellá-Aucejo Á, Bernardos A, Martínez-Mañez R, Mateo J, Herranz N. Harnessing senolytics and PARP inhibition to expand the antitumor activity of CDK4/6 inhibitors in prostate cancer. Mol Cancer Ther. 2025 Jul 2. doi: 10.1158/1535-7163.MCT-24-0903. Epub ahead of print.

About VHIO

The Vall d’Hebron Institute of Oncology (VHIO), established in 2006 and located within the Vall d’Hebron Campus, is a reference comprehensive cancer center for personalized medicine in oncology. Through our purely translational and multidisciplinary research model, we aim to improve the prevention, early diagnosis and treatment of cancer by transforming the latest scientific discoveries made in the laboratory into early phase clinical trials for the development of more effective therapies to improve the quality of life and survival  of cancer patients.

VHIO forms part of the CERCA – Research Centres of Catalonia system and is accredited as a Severo Ochoa Center of Excellence.

Research at VHIO would not be possible without the support received from our patrons –Generalitat de Catalunya, Fundació Privada CELLEX, "La Caixa" Foundation, Fundación FERO, Fundación BBVA and the CRIS Cancer Foundation– and the public funding it receives as well as the generous support from institutional supporters, private institutions, companies, associations, societies, and individual donors. Only with such continued support will VHIO continue to advance personalized and targeted therapies against cancer.

 

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